Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18]#[N:19].CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][CH2:17][C:18]#[N:19]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCOc1ccc(Cl)c(Cl)c1
Temperature: 70 °C
Yield: 90.6 %

Procedure:
A mixture of 81.5 g of 3,4-dichlorophenol, 98.0 g of anhydrous K2CO3, 40.0 g of chloroacetonitrile and 100 ml of DMSO was stirred and heated to 70° C. after an initial period of ice cooling. The reaction mixture was heated at 70°-80° C. for 3 hours and the reaction mixture was then poured into 2500 ml of ice and water which resulted in crystal formation. The crystals were removed by filtration, washed with water and then dried overnight in a vacuum oven. The resulting solids were put in approximately 1 liter of boiling cyclohexane and treated with activated charcoal and then filtered. The filtrate was cooled to 10° C. and filtered, which gave 91.5 g of 3,4-dichlorophenoxyacetonitrile, m.p. 61°-62° C.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.[Cl:16]CCl>C(Cl)(=O)C(Cl)=O.CN(C=O)C>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([Cl:16])=[O:15]
Reactant: ClCCl
Reactant: O=C(O)CCCCCN1C(=O)C=CC1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a stirring solution of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoic acid (3.15 g, 14.9 mM) in 15 mL of dichloromethane, oxalyl chloride (1.61 mL, 17.9 mM) was added followed by one drop of DMF. The reaction was allowed to stir at room temperature for three hours. The reaction was concentrated in vacuo. The residue was dissolved in a one to one solution of heptane and dichloromethane and then concentrated in vacuo. This process was repeated two more times producing a solid #248 (3.43 g, 100%). 1H NMR (400 MHz, DMSO-d6): δ [7.02 (s, 2H), 3.43 (m, 2H), 2.53 (m, 1H), CH2.18 (m, 1H), 1.54 (m, 4H), 1.26 (m, 2H).]
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([CH3:14])=[CH:11][C:12]#[N:13])[CH:6]=[CH:7][CH:8]=1.[CH:17]([C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)=O.[C:27]([CH2:29][C:30]([NH2:32])=[O:31])#[N:28].N1CCCCC1>C(O)C>[NH2:28][C:27]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:4]=2)[C:10]([CH3:14])=[C:11]([C:12]#[N:13])[CH:17]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[C:29]=1[C:30]([NH2:32])=[O:31]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: N#CCC(N)=O
Reactant: CC(=CC#N)Nc1cccc(C(F)(F)F)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)C(C(N)=O)=C(N)N1c1cccc(C(F)(F)F)c1

Procedure:
Under argon, 100 mg (0.44 mmol) of the compound of Example 2A, 57.97 mg (0.44 mmol) 4-formylbenzonitrile and 37.17 mg (0.44 mmol) 2-cyanoacetamide are dissolved in 2 ml ethanol. 3.76 mg (4.4 μl, 0.04 mmol) piperidine are added and the mixture is stirred at reflux overnight. The product is crystallised from the reaction mixture at 4° C. The formed crystals are filtered, washed twice with ethanol and dried. The crude product is purified by column chromatography with dichloromethane/methanol 100:1 as eluent.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][NH:10]2)[CH:4]=1)#N.[OH-:21].[Na+].Cl.[OH2:24]>C(O)C>[O:14]=[C:13]1[N:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][N:6]=2)[C:1]([OH:24])=[O:21])[NH:10][CH:11]=[C:12]1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#Cc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1

Procedure:
200 mg (760 μmol) of the compound from Example 29 are suspended in a mixture of 6 ml ethanol and 4 ml water, 0.6 ml 50% strength sodium hydroxide solution are added and the mixture is heated under reflux for 1 h. After cooling, a weakly acid pH is established with 1 M hydrochloric acid and the precipitate is filtered off with suction, washed with water and dried.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1I)([CH3:4])([CH3:3])[CH3:2].[CH:17]#[C:18][CH2:19][CH3:20].C(N(CC)CC)C>C1(C)C=CC=CC=1.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]([C:13]1[CH:12]=[C:11]([Cl:15])[N:10]=[CH:9][C:8]=1[NH:7][C:6](=[O:16])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])#[C:18][CH2:19][CH3:20]
Reactant: C#CCC
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCC#Cc1cc(Cl)ncc1NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a deoxygenated solution of (6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (6.0 g, 16.9 mmol), 1-butyne (9 g, 169 mmol), CuI (160.1 mg, 0.84 mmol) and triethylamine (3.4 g, 33.2 mmol) in toluene (40 mL) and water (14 mL) was added Pd(PPh3)2Cl2 (592 mg, 0.84 mmol) under N2 in a autoclave. The mixture was heated to 70° C. and stirred for 24 h. The solid was filtered off and washed with ethyl acetate (60 mL×3). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 10/1) to give tert-butyl 4-(but-1-ynyl)-6-chloropyridin-3-ylcarbamate (3.5 g, 74%). 1H-NMR (CDCl3, 300 MHz) δ 9.13 (s, 1H), 7.22 (s, 1H), 6.98 (s, 1H), 2.53 (q, J=7.5 Hz, 2H), 1.54 (s, 9H), 1.29 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[N:9][OH:10])[CH3:2].[Cl:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16]>C(Cl)(Cl)Cl.C(#N)C.C(N(CC)CC)C>[CH2:1]([N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[N:9][O:10][C:15](=[O:16])[NH:14][CH2:13][CH2:12][Cl:11])[CH3:2]
Reactant: O=C=NCCCl
Reactant: CCN1C(=O)CSC1=NO
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN1C(=O)CSC1=NOC(=O)NCCCl
Reaction time: 8 h

Procedure:
A solution of 2.0 g, 3-ethyl-2-oximino-4-thiazolidinone in 100 ml chloroform, 50 ml acetonitrile, 1.32 g., 2-chloroethylisocyanate and 2 drops of triethyl amine was placed in a pressure bottle and left standing overnight at ambient temperature. Concentration yielded 3.0 g of product. Recrystallized from isopropylether - ethyl acetate, m.p. 99°-102°C.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.[CH:21]1([C:24]([NH2:32])([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH3:25])[CH2:23][CH2:22]1>>[CH:21]1([C:24]([NH:32][C:12](=[O:14])[C:9]2[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([C:2]3([F:1])[CH2:3][CH2:4][CH2:5]3)=[CH:11][N:10]=2)([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH3:25])[CH2:23][CH2:22]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(F)CCC2)cn1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3(F)CCC3)cn2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(1-fluorocyclobutyl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (example 285a) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and the racemate was separated into its enantiomers by preparative chiral HPLC (Chiralpak AD, ethanol/heptane). The title compound was the first enantiomer collected; MS (ESI, m/z): 443.3 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.CN(C=O)C>CCOC(C)=O.O>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:17]([F:16])([F:26])[F:27])=[CH:20][CH:21]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(OC(F)(F)F)cc1
Reaction time: 12 h

Procedure:
tert-Butyl bromoacetate was added to a stirring suspension of potassium carbonate (14.6 g, 106 mmol), 4-(trifluoromethoxy)phenol (15.7 g, 88 mmol) and DMF (50 mL). The reaction mixture was stirred for 12 hours. The mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with 3×EtOAc. The combined organic layers were washed with 5% aqueous lithium chloride and brine, dried over sodium sulfate, filtered, and reduced in vacuo to afford the title compound as a colorless oil: 1H NMR (400 MHz, d6-DMSO): 7.27 (d, 2H), 6.98 (d, 2H), 4.68 (s, 2H), 1.42 (s, 9H).
Reaction SMILES: O[C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S(Cl)([Cl:17])=O.[N:19]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl.CN(C=O)C>[Cl:17][C:2]1[CH:11]=[C:10]([C:12]([NH:26][CH2:25][CH2:24][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1cc(O)nc2ccccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCCN1CCCC1)c1cc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To a stirred suspension of 2-hydroxyquinoline-4-carboxylic acid (preparation 10) (2.20 g, 12 mmol) in anhydrous DCM (60 ml), was added anhydrous DMF (36 drops) and thionyl chloride (3.3 ml, 46 mmol) under argon at room temperature. The mixture was refluxed for 3 h and then allowed to cool to room temperature. The solvents were removed under reduced pressure and the residue was dissolved in anhydrous THF (37 ml) under argon. 2-Pyrrolidin-1-ylethanamine (4.4 ml, 35 mmol) was added and the reaction was stirred at room temperature for 16 h. Solvents were removed under vacuum and the residue partitioned between NaHCO3 saturated aqueous solution (100 ml) and DCM (2×100 ml). The organic layers were combined, dried over MgSO4, filtrated and evaporated under reduced pressure. The crude was purified by column chromatography using a 24 g silica gel cartridge. Solvent A: DCM, Solvent B: 10% MeOH—NH3 in DCM. Gradient: 2 min hold 100% A followed by 18 min ramp to 40% B and then hold 5 min at 40% B. The desired fractions were combined and concentrated to dryness under reduced pressure to obtain the desired material as a white solid (2 g, 6.6 mmol, 56%).
Reaction SMILES: [CH:1]1([C:7]2([C:13](Cl)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:16][CH:17]1[CH2:22][NH:21][C:20](=[N:23][N+:24]([O-:26])=[O:25])[NH:19][CH2:18]1.CN(C=O)C>C(#N)C>[CH:1]1([C:7]2([C:13]([O:16][CH:17]3[CH2:18][NH:19][C:20](=[N:23][N+:24]([O-:26])=[O:25])[NH:21][CH2:22]3)=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)C1(C2CCCCC2)CCCCC1
Reactant: O=[N+]([O-])N=C1NCC(O)CN1
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(OC1CNC(=N[N+](=O)[O-])NC1)C1(C2CCCCC2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of 1-cyclohexylcyclohexane-1-carbonyl chloride (2.1 g) in acetonitrile (30 ml), 5-hydroxy-2-nitroiminohexahydropirimidine (1.28 g) was added portionwise. The mixture was stirred at room temperature overnight, then DMF (10 ml) was added and the mixture was heated to 50° C. for 24 hours. The reaction was quenched with water. The precipitate was collected, dried and triturated with diethyl ether to afford 0.93 g of 2-nitroiminohexahydropyrimidin-5-yl 1-cyclohexylcyclohexane-1-carboxylate.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][O:5][C:6](=[O:28])[C:7](=[O:27])[C:8]1[S:9][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[CH:11][CH:12]=1.[CH3:30][I:31]>CC(C)=O>[I-:31].[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[O:16][CH2:15][CH2:14][O:13][C:10]1[S:9][C:8]([C:7](=[O:27])[C:6]([O:5][CH2:4][CH2:3][N+:2]([CH3:30])([CH3:29])[CH3:1])=[O:28])=[CH:12][CH:11]=1
Reactant: CI
Reactant: CN(C)CCOC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Solvent: CC(C)=O
Product: C[N+](C)(C)CCOC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Product: [I-]
Yield: 67 %

Procedure:
A solution of 5-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxo-2-thiopheneacetic acid 2-(dimethylamino)ethyl ester (0.4 g) and methyl iodide (0.15 g) in acetone (7 mL) was stirred overnight at room temperature. The resulting yellow crystalline solid was filtered off, washed with acetone and then crystallized from methanol to afford 0.36 g of 2-[[5-[[2-(2naphthalenyloxy)ethyl]oxy]-alpha-oxo-2-thiopheneacetyl]oxy]-N,N,N-trimethylethanaminium iodide, mp 169°-170 ° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[O:7]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C-:22]#[N:23].[Na+]>O.ClCCl>[N:1]1([CH:17]([C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:15]=2)[C:22]#[N:23])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: C1CCNC1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CC(c1cccc(Oc2ccccc2)c1)N1CCCC1
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A solution of pyrrolidine (2.13 g, 30 mmole) in water (10 ml) was neutralised with concentrated hydrochloric acid. 3-Phenoxybenzaldehyde (3.96 g; 20 mmole) was added to the stirred solution followed by sodium cyanide (1.5 g; 30 mmole) and "Teric" N8 (5 drops of a 10% aqueous solution). The mixture was stirred vigorously for a period of 1 hour and then dichloromethane (50 ml) was added. The organic phase was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to give the title compound as a yellow oil (5.0 g). Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.8 (4H, m, pyrrolidine ring β-protons); 2.6 (4H, m, pyrrolidine ring α-protons); 5.0 (1H, s, CH); 7.0-7.6 (9H, m, aromatic protons). Infra-red spectrum (liquid film; νmax in cm-1): 2950 (m) (m); 2800(m); 1580(s); 1480(s); 1240(s); 840(m); 740(m).
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C@@:7]23[CH2:26][N:20]([C@H:21]([C:23](O)=[O:24])[CH2:22]2)[C:19](=[O:27])[C@@H:18]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][S:8]3)=[CH:3][CH:2]=1.[NH2:42][C@:43]1([C:48]([NH:50][S:51]([CH:54]2[CH2:56][CH2:55]2)(=[O:53])=[O:52])=[O:49])[CH2:45][C@H:44]1[CH:46]=[CH2:47].CC1C=CC(S(O)(=O)=O)=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CCOC(C)=O>[C:1]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:6]=[CH:5][C:4]([C@@:7]23[CH2:26][N:20]([C@H:21]([C:23](=[O:24])[NH:42][C@:43]4([C:48](=[O:49])[NH:50][S:51]([CH:54]5[CH2:56][CH2:55]5)(=[O:53])=[O:52])[CH2:45][C@H:44]4[CH:46]=[CH2:47])[CH2:22]2)[C:19](=[O:27])[C@@H:18]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][S:8]3)=[CH:3][CH:2]=1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCCCCCS[C@@]2(c3ccc(-c4ccccc4)cc3)C[C@@H](C(=O)O)N(C2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(c3ccc(-c4ccccc4)cc3)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCCCCCCCCS2)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
To an iced slurry of (3S,14R,16S)-14-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadecane-16-carboxylic acid (20 mg, 0.034 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide, pTSA, 0.68H2O (17.85 mg, 0.043 mmol), and HATU (32.5 mg, 0.0855 mmol) in DCM (1 mL) was added N,N-Diisopropylethylamine (0.030 mL, 0.172 mmol). The formed light brown solution was stirred at room temperature overnight. Diluted with EtOAc, washed it with 5% citric acid, and brine, dried over MgSO4, filtered, evaporated. The formed residue was purified by prep-HPLC to afford the desired product tert-butyl (3S,14R,16S)-14-(biphenyl-4-yl)-16-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadecan-3-ylcarbamate (7 mg, 8.65 mmol, 25.1% A yield) as a white foam. 1H NMR (400 MHz, MeOD) δ ppm 0.94-1.37 (m, 13 H) 1.35-1.63 (m, 12 H) 1.84 (dd, J=8.16, 5.40 Hz, 1 H) 1.91-2.08 (m, 4 H) 2.08-2.19 (m, 1 H) 2.19-2.45 (m, 4 H) 2.59 (dd, J=12.30, 6.53 Hz, 1 H) 2.82-2.99 (m, 1 H) 3.87 (dd, J=10.29, 6.53 Hz, 1 H) 4.00-4.22 (m, 2 H) 4.64 (t, J=8.53 Hz, 1 H) 5.07 (dd, J=10.29, 1.51 Hz, 1 H) 5.24 (dd, J=17.19, 1.38 Hz, 1 H) 5.60-5.78 (m, 1 H) 6.36 (d, J=8.53 Hz, 1 H) 7.32 (t, J=7.28 Hz, 1 H) 7.42 (t, J=7.53 Hz, 2 H) 7.53-7.74 (m, 6 H); LC-MS (retention time: 3.50 min, method C), MS m/z 793.5 (M+H), 737 (M-t-Bu), 693 (M-BOC).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])/[CH:4]=[C:5](\[CH3:8])/[CH2:6]O.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)[Cl:32]>>[CH3:1][O:2][C:3](=[O:9])/[CH:4]=[C:5](\[CH3:8])/[CH2:6][Cl:32]
Reactant: ClCCl
Reactant: COC(=O)/C=C(\C)CO
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)/C=C(\C)CCl
Reaction time: 2 h

Procedure:
To (E)-4-hydroxy-3-methyl-2-butenoic acid methyl ester (0.75 g, 5.76 mmol) in methylene chloride cooled to -15° C. in a flame dried flask is added dibromotriphenylphosphorane (2.68 g, 6.34 mmol). The reaction is stirred at -15° C.-0° C. for two hours, quenched by addition of ice (10 ml), extracted with methylene chloride (2×10 ml), washed with saline (10 ml), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (95/5). The appropriate fractions are combined and concentrated in vacuo to give (E)-4-chloro-3-methyl-2-butenoic acid methyl ester. 4-Amino-6-chloro-2-mercaptopyrimidine mesylate (0.30 g, 1.16 mmol) is dissolved in DMF (4 ml) and sodium hydride (0.06 g, 2.56 mmol) at ambient temperature followed by the addition of (E)-4-bromo-3-methyl-2-butenoic acid methyl ester (0.22 g, 1.16 mmol). The reaction is stirred for 15 hours, quenched with excess water, extracted with ethyl acetate (3×20 ml). The extracts are combined, washed with saline (20 ml), dried over sodium sulfate, concentrated in uacuo and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (80/20). The appropriate fractions are combined (Rf =0.43, TLC, hexane/ethyl acetate, 50/50) and concentrated in vacuo to give the title compound, mp 134-136° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: C1COCCN1
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(-c3ccc(CN4CCOCC4)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.9 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), morpholine (0.024 mL, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.409 mmol) in dichloroethane (1.4 mL) was shaken at ambient temperature for 16 h. Additional portions of morpholine (0.012 mL, 0.14 mmol), sodium triacetoxyborohydride (0.043 g, 0.20 mmol), and acetic acid (0.016 mL) were added and the reaction mixture was stirred at ambient temperature for 24 h. 1 N NaOH (1 mL) was added and the reaction mixture was filtered to afford a gray solid which was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 10-60% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 21-23 min was collected, concentrated, and lyopholized to afford N1-(4-{4-amino-1-[4-(morpholinomethyl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.007 g, 0.011 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.93 (1H, s), 8.34-8.37 (2H, m), 8.14-8.18 (2H, m), 7.97-8.02 (1H, m), 7.87-7.91 (1H, m), 7.73-7.76 (1H, m), 7.45-7.51 (2H, m), 7.44 (1H, s), 7.38-7.43 (1H, m), 3.41-3.59 (8H, m), and 3.36 (2H, s); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 11.72 min. MS: MH+ 622.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])C.[C:28](Cl)(=[O:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1COCC1>[C:1]([O:5][C:6]([NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[N:10]([C:28]([C:29]2[CH:37]=[CH:36][C:32]([C:33]([N:23]3[C:24]4[CH:25]=[CH:18][CH:19]=[CH:11][C:12]=4[NH:13][C:14](=[O:15])[C@@H:27]([NH:7][C:6](=[O:20])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:26]3)=[O:34])=[CH:31][CH:30]=2)=[O:38])[CH2:9]1)=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc4ccccc43)cc2)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.8 %

Procedure:
To ((S)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester (Intermediate 2) (57.9 mg, 0.209 mmol) and triethylamine (29.1 μL, 0.209 mmol) in anhydrous THF (1 mL) was added terephthaloyl dichloride (21.2 mg, 0.104 mmol). The resulting suspension was stirred at room temperature for 4 h. The mixture was concentrated and the residue was triturated with water. The solid was collected, washed with water and purified by silica gel chromatography to provide tert-butyl N-[(3S)-5-[4-[(3S)-3-(tert-butoxycarbonylamino)-2-oxo-3,4-dihydro-1H-1,5-benzodiazepine-5-carbonyl]benzoyl]-2-oxo-3,4-dihydro-1H-1,5-benzodiazepin-3-yl]carbamate as a white solid (27.6 mg, 39%).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(O)=O.[CH2:12]=[CH:13][CH2:14][CH3:15]>>[C:1]([O:8][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: CC(=O)CCC(=O)O
Reactant: C=CCC
Solvent: O=CO
Product: CCCCOC(=O)CCC(C)=O
Temperature: 100 °C

Procedure:
A 5 cc autoclave is charged with 2 cc of an aqueous solution containing 0.5 mmoles of levulinic acid and 2 mmoles of formic acid. 15 wt. % ZSM-5 zeolite is added as a catalyst. The reactor is pressurized to 0.69 MPa with 1-butene and heated to 100° C. for 4 hours while maintaining a constant pressure of 1-butene. After cooling, the organic phase is separated. A mixture of butyl formate and butyl levulinate is formed as product.